Suppressor of cytokine signaling-1 attenuates the duration of interferon γ signal transduction in vitro and in vivo

Suppressor of cytokine signaling-1 (SOCS-1) is a cytokine-inducible intracellular protein that functions to negatively regulate cytokine signal transduction pathways. Studies in vitro have shown that constitutive over expression of SOCS-1 inhibits signaling in response to a range of cytokines, including interferons (IFN). Mice lacking SOCS-1 die from a complex disease characterized by liver degeneration and massive inflammation. Whereas there is clear evidence of increased IFN gamma signaling in SOCS-1(-/-) mice, it is unclear to what extent this is due to increased IFN gamma levels or to increased IFN gamma sensitivity. Here we have used SOCS-1(-/-) IFN gamma (-/-) mice, which remain healthy and produce no endogenous IFN gamma to demonstrate that in vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFN gamma and that this correlates with a dramatically increased sensitivity to the toxic effects of IFN gamma in vivo. Thus, SOCS-1 is required for the timely attenuation of IFN gamma signaling in vivo.